Mapping the early life gut microbiome in neonates with critical congenital heart disease: multiomics insights and implications for host metabolic and immunological health
Yuan Huang,
Wenlong Lu,
Min Zeng,
Xiaoyue Hu,
Zhanhao Su,
Yiwei Liu,
Zeye Liu,
Jianhui Yuan,
Li Li,
Xiaoling Zhang,
Long Huang,
Wanjin Hu,
Xu Wang,
Shoujun Li,
Hao Zhang
Affiliations
Yuan Huang
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Wenlong Lu
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Min Zeng
PICU, Pediatric Cardiac Center, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College
Xiaoyue Hu
Department of Neonatology, Affiliated Children’s Hospital of Capital Institute of Pediatrics
Zhanhao Su
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Yiwei Liu
Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children’s Medical Center, National Children’s Medical Center, Shanghai Jiaotong University School of Medicine
Zeye Liu
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Jianhui Yuan
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Li Li
Department of Neonatology, Affiliated Children’s Hospital of Capital Institute of Pediatrics
Xiaoling Zhang
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Long Huang
Shanghai Majorbio Bio-Pharm Technology Co
Wanjin Hu
Shanghai Majorbio Bio-Pharm Technology Co
Xu Wang
PICU, Pediatric Cardiac Center, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College
Shoujun Li
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Hao Zhang
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Pediatric Cardiac Surgery Center, Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College
Abstract Background The early life gut microbiome is crucial in maintaining host metabolic and immune homeostasis. Though neonates with critical congenital heart disease (CCHD) are at substantial risks of malnutrition and immune imbalance, the microbial links to CCHD pathophysiology remain poorly understood. In this study, we aimed to investigate the gut microbiome in neonates with CCHD in association with metabolomic traits. Moreover, we explored the clinical implications of the host-microbe interactions in CCHD. Methods Deep metagenomic sequencing and metabolomic profiling of paired fecal samples from 45 neonates with CCHD and 50 healthy controls were performed. The characteristics of gut microbiome were investigated in three dimensions (microbial abundance, functionality, and genetic variation). An in-depth analysis of gut virome was conducted to elucidate the ecological interaction between gut viral and bacterial communities. Correlations between multilevel microbial features and fecal metabolites were determined using integrated association analysis. Finally, we conducted a subgroup analysis to examine whether the interactions between gut microbiota and metabolites could mediate inflammatory responses and poor surgical prognosis. Results Gut microbiota dysbiosis was observed in neonates with CCHD, characterized by the depletion of Bifidobacterium and overgrowth of Enterococcus, which was highly correlated with metabolomic perturbations. Genetic variations of Bifidobacterium and Enterococcus orchestrate the metabolomic perturbations in CCHD. A temperate core virome represented by Siphoviridae was identified to be implicated in shaping the gut bacterial composition by modifying microbial adaptation. The overgrowth of Enterococcus was correlated with systemic inflammation and poor surgical prognosis in subgroup analysis. Mediation analysis indicated that the overgrowth of Enterococcus could mediate gut barrier impairment and inflammatory responses in CCHD. Conclusions We demonstrate for the first time that an aberrant gut microbiome associated with metabolomic perturbations is implicated in immune imbalance and adverse clinical outcomes in neonates with CCHD. Our data support the importance of reconstituting optimal gut microbiome in maintaining host metabolic and immunological homeostasis in CCHD. Video Abstract